Nicotinamide Riboside Shows Effects on Hippocampal Features but Not Improved Memory

Christopher Martens, PhD

New data from a 12-week, double-blind, randomized phase 2 trial showed that nicotinamide riboside (NR) supplementation was safe and well tolerated in adults with amnestic mild cognitive impairment (aMCI) and led to enhanced perfusion of the hippocampus. Despite this, investigators found no effects on improved memory performance and concluded that additional, larger studies are needed to further determine the efficacy of NR.¹

NR is a vitamin B3 derivative and a precursor to nicotinamide adenine dinucleotide (NAD+), a coenzyme essential for energy metabolism, DNA repair, and cell survival. The goal of NR supplementation is to replenish NAD+, thereby supporting healthier brain metabolism and cellular resistance. Boosting NAD+ with NR has been thought to enhance mitochondrial energy production, reduce inflammation, support neuronal survival, and potentially slow cognitive decline.

The study, presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31, in Toronto, Canada, the trial featured 52 older adults with MCI who were randomly assigned to either NR at 500 mg BID or placebo for a 12-week period. Following treatment, blood NAD+ increased with NR (pre: 23.36 [±1.94]; post: 48.52 [±4.12] uM) compared with placebo (pre: 24.12 [±1.70]; post: 25.14 [±1.58] uM), with a significant treatment by time interaction (P <.001).

Led by Christopher Martens, PhD, an assistant professor at the University of Delaware, 42 patients completed the 12-week study, with a similar adherence rate observed in each group (NR = 85% [±20%] vs placebo = 91% [±5%]). In the trial, those randomized to NR showed increases in perfusion of the left hippocampus (pre: 51.7 [±3.3]; post: 58.0 [±3.8] ml/min/100 g) compared with placebo (pre: 55.6 [±2.8]; post: 51.7 [±2.3] ml/min/100 g; interaction, P = .033); however, this did not lead to change in memory performance.

Martens and colleagues did however observe a modest increase in delayed recall memory on the WMS-IV in the NR group (interaction P = .062) despite not seeing significant improvements in cognitive function. They also noted that the effects seen on hippocampus were not strongly influenced by baseline plasma phosphorylated tau (p-tau) 217, a notable biomarker for AD pathology. Treatment with NR was considered safe, with no serious adverse events reported and a comparable safety profile to that of placebo.

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The study authors concluded that a larger phase 3 trial would be needed to further determine the efficacy of NR in delaying cognitive impairment due to Alzheimer disease related dementias. Prior to this study, the use of NA in cognitive contexts was also evaluated in a phase 2a proof-of-concept trial, which was presented at AAIC 2023.²

That study, led by Joshua D. Grill, PhD, professor of neurobiology and behavior and the University of California, Irvine, featured 47 individuals with early AD who received either 1500 mg twice daily of nicotinamide or placebo, for a 12-month period. On the primary outcome of change in cerebrospinal fluid p-tau231, no statistically significant difference was observed on ANCOVA models (mean difference, 2.06 [SE, 4.03]; P = .61); although, greater mean declines were found in the nicotinamide arm (–4.7 [±14.5]) than placebo (–2.3 [±10.6]).

In the proof-of-concept study, Nicotinamide was associated with significantly less change on CDR-SB (estimate, –1.42 [SE, 0.65]; P = .03) but not on cognitive or functional assessments, explained through the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (estimate, –1.93 [SE, 1.93]; P = .32) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living for Mild Cognitive Impairment scale (estimate, –3.10 [SE, 1.86]; P = .10). Overall, there were no significant effects on CSF p-tau181, amyloid-ß (Aß)40, Aß42, and total tau (all P >.05); however, mean changes in CSF p-tau181 (0.4 [±29.8] vs 10.4 [±41.8]) and total tau (8.4 [±228.6] vs 60.5 [±237.5]) favored nicotinamide.

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REFERENCES
1. Martens CR, Decker KP, DeConne TM, et al. A phase-II randomized controlled pilot and feasibility study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment. Presented at: AAIC 2025; July 27-31; Toronto, Canada. Abstract 108851
2. Grill JD, Tam S, Thai B, et al. A phase 2a proof-of-concept double-blind, randomized, placebo-controlled trial of nicotinamide in early Alzheimer’s disease. Presented at: AAIC 2023; June 16-20; Amsterdam, Netherlands. Abstract 77979